期刊
PEPTIDES
卷 28, 期 5, 页码 1012-1019出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.peptides.2007.02.001
关键词
osteoporosis; peak bone mass; mu CT; obesity
资金
- NIAAA NIH HHS [R01 AA011140, R01 AA011140-10, AA 011140] Funding Source: Medline
- NIDDK NIH HHS [DK 37273, R01 DK037273-16, R01 DK037273] Funding Source: Medline
- PHS HHS [27372] Funding Source: Medline
Skeletal growth is tightly coupled to energy balance via complex and incompletely understood mechanisms. Leptin- deficient ob/ob mice are obese and develop multiple pathologies associated with the metabolic syndrome. Additionally, ob/ob mice have skeletal abnormalities. The objective of this study was to evaluate the effects of leptin deficiency and long duration selective central leptin repletion via recombinant adeno-associated virus-leptin (rAAV-lep) gene therapy on bone in growing ob/ob mice. The ob/ob mice were injected in the hypothalamus with either rAAV-lep orrAAV-GFP (control vector). Treated ob/ob and untreated wild-type (WT) mice were then maintained on a normal diet for IS weeks. In a second experiment, similarly treated mice along with a group of pair-fed mice were maintained for 30 weeks. Leptin was not detected in blood of either rAAV-lep- or rAAVGFP-treated mice although rAAV-lep-treated mice displayed leptin transgene expression in the hypothalamus. As expected, rAAV-lep normalized body weight and food intake. Compared to WT mice, rAAV-GFP-treated ob/ob mice had decreased femoral length (by 1.6 mm or 10%, P < 0.001), decreased total femur bone volume (by 3.3 mm(3) or 19%, P < 0.001), but increased cancellous bone volume in the distal femur (by 0.04 mm(3) or 60%, P < 0.09) and lumbar vertebrae (by 0.26 mm(3) or 118%, P < 0.001). Treatment with rAAV-lep rescued the ob/ ob skeletal phenotype by increasing femoral length and total bone volume, and decreasing femoral and vertebral cancellous bone volume, so that at 15 weeks post-rAAV-lep injection the ob/ob mice no longer differed from WT mice. No further skeletal changes in either the femur or lumbar vertebra were observed at 30 weeks post-rAAV-lep administration. The results suggest that hypothalamic leptin functions as an essential permissive factor for normal bone growth. (c) 2007 Elsevier Inc. All rights reserved.
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